Bub1 overexpression induces aneuploidy and tumor formation through Aurora B kinase hyperactivation.
Bub1 overexpression induces aneuploidy and tumor formation through Aurora B kinase hyperactivation.
复制标题
DOI：
10.1083/jcb.201012035
复制
发表时间：
2011-06-13
期刊：
影响因子：
--
通讯作者：
van Deursen JM
中科院分区：
文献类型：
--
作者：
Ricke RM;Jeganathan KB;van Deursen JM
激活的Aurora B激酶是Bub1过表达诱导小鼠非整倍体和肿瘤发生的主要介质。蛋白激酶Bub1在多种人类肿瘤中都有高表达，且常与不良的临床预后相关，但其分子和细胞后果以及在肿瘤发生中的作用尚不清楚。在这里，我们证明了在小鼠中过表达Bub1会导致近二倍体的非整倍体和肿瘤的形成。我们发现，染色体错位和滞后是导致观察到的非整倍化的主要有丝分裂错误。高Bub1水平导致Bub1激酶活性异常和Aurora B激酶过度激活。当Aurora B活性被抑制时，无论是药物上的还是通过BubR1的过表达，Bub1过表达引起的染色体分离错误都会在很大程度上得到纠正。重要的是，过量表达Bub1的转基因小鼠发生了各种类型的自发肿瘤，并表现出加速的Myc诱导的淋巴肿大。我们的结果证实了Bub1具有致癌特性，并表明Aurora B是过表达的Bub1驱动非整倍化和肿瘤发生的关键靶点。
Hyperactivated Aurora B kinase is a primary mediator of Bub1 overexpression-induced aneuploidy and tumorigenesis in mice. High expression of the protein kinase Bub1 has been observed in a variety of human tumors and often correlates with poor clinical prognosis, but its molecular and cellular consequences and role in tumorigenesis are unknown. Here, we demonstrate that overexpression of Bub1 in mice leads to near-diploid aneuploidies and tumor formation. We found that chromosome misalignment and lagging are the primary mitotic errors responsible for the observed aneuploidization. High Bub1 levels resulted in aberrant Bub1 kinase activity and hyperactivation of Aurora B kinase. When Aurora B activity is suppressed, pharmacologically or via BubR1 overexpression, chromosome segregation errors caused by Bub1 overexpression are largely corrected. Importantly, Bub1 transgenic mice overexpressing Bub1 developed various kinds of spontaneous tumors and showed accelerated Myc-induced lymphomagenesis. Our results establish that Bub1 has oncogenic properties and suggest that Aurora B is a critical target through which overexpressed Bub1 drives aneuploidization and tumorigenesis.
登录
查看更多内容
影响因子：
4
作者：
Cimini, D;Moree, B;Salmon, ED
通讯作者：
Salmon, ED
DOI：
10.1083/jcb.153.4.865
发表时间：
2001-05-14
期刊：
The Journal of cell biology
影响因子：
--
作者：
Adams RR;Maiato H;Earnshaw WC;Carmena M
通讯作者：
Carmena M
影响因子：
7.5
作者：
Carmena M;Ruchaud S;Earnshaw WC
通讯作者：
Earnshaw WC
影响因子：
64.8
作者：
Cahill, DP;Lengauer, C;Vogelstein, B
通讯作者：
Vogelstein, B
影响因子：
8
作者：
Agarwal, ML;Agarwal, A;Stark, GR
通讯作者：
Stark, GR